This invention relates to medical screening.
Various medical conditions are the subject of routine screening of populations of patients who are potential candidates for the particular condition. For example, in the United States women are routinely screened for cervical cancer.
Carcinoma of the cervix is one of the most common malignancies in women. Worldwide, an estimated 470,000 women develop cervical cancer each year, with more than 80% of these cancers occurring in the developing world. In general, cervical cancer progresses slowly through several well-defined stages, and thus early detection permits the cancerous lesions to be treated with nearly 100% success. The initiation of mass screening has reduced cervical cancer mortality in the United States by 50% over the last 30 years (Kavita, et al., Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Int Med 2000; 132(10):810-819). However, many countries lack the medical infrastructure or technical expertise to carry out effective mass screening (Michelow, et al., Simulation of primary cervical cancer screening by the PAPNET system in an unscreened, high-risk community. Acta Cytol 1997; 41(1):88-92; Veneti, et al., PAPNET for cervical cytology screening: experience in Greece. Acta Cytol 1999; 43(1):30-33; Denny, et al., Two-stage cervical cancer screening: an alternative for resource-poor settings. Am J Obst Gyn 2000;183(2):383-388). As a result, cervical cancer is the leading cancer-related cause of death in women of the developing world. (Denny, et al., supra).
The standard method of cervical cancer screening uses the Pap smear, named after Dr. George Papanicolaou, who introduced it into clinical practice in the 1930s. Pap smear screening is presently a two-step process of collection and inspection. First, a physician or other trained medical professional collects a sample of cells from the cervix of the patient using an ectocervical spatula, an endocervical brush, and/or cotton swabs. Once collected, the specimen is processed by placing a portion of the sample on a dry glass slide, fixing it with a preservative, placing a cover slide on the sample, and staining it. Once the slide has been prepared and stained, it is manually screened by a cytotechnologist, under a microscope, for potentially abnormal cells. Suspicious cells may be further examined by a cytopathologist. Once a determination of the status of the sample is made, a report is produced that is normally sent to the referring physician or clinic.
There are inherent limitations in this standard screening approach related to the quality of the sample, the quality of the slide, and the effectiveness of the screener. The standard technique of placing the sampling spatula or brush on the glass slide results in capture of only the cells that are in contact with the slide. There is generally no proportional representation on the slide of all the cells taken from the cervix. In some cases, an inadequate number of cells are preserved on the slide, resulting in the need for re-screening. Even when the number of cells is adequate, the appearance of the resultant slide can be highly variable. The cells may be clumped, overlapping, and poorly preserved. Visibility may be partially obscured by blood, inflammation or drying artifacts.
There are several factors that limit the effectiveness of the slide screener. First, a typical Pap smear slide contains up to 300,000 cells. With a limited amount of time to screen each slide, the screener cannot examine each cell, but instead must do a quick overall scan of the slide and then sample the most promising areas at greater magnification looking for abnormal cells. Second, the screener must cope with habituation (the expectation of a negative result) and fatigue.
These limitations affect both the sensitivity and specificity of testing. Sensitivity refers to the proportion of cellular abnormalities that are actually detected. Sensitive tests reduce the number of false negativesxe2x80x94slides reported as being within normal limits when, in reality, there were cells indicative of abnormal changes. Specificity refers to the proportion of normal slides that are actually reported as normal. Specific tests have a low rate of false positivesxe2x80x94reports of findings that require follow-up when, in fact, the smear was normal.
While the upper limit of sensitivity in Pap smear screening is 95% due to inherent sampling error (Godfrey S E, The Pap smear, automated rescreening and negligent nondisclosure. Am J Clin Pathol 1999; 111:14-17), the actual sensitivity rate for standard screening ranges from 30-93% in the United States, with the specificity of standard screening at between 86-100% (Sprenger, et al., The false-negative rate in cervical cytology: comparison of monolayers to conventional smears. Acta Cytol 1996;40:81-89; AHCPR, Evaluation of cervical cytology. Summary, Evidence Report/Technology Assessment: Number 5. Agency for Health Care Policy and Research, Rockville, Md. January 1999. http://www.ahrq.gov/clinic/cervsumm.htm.; Nanda, et al., Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Int Med 2000;132(10):810-819). There is little information on quality control and therefore sensitivity outside the United States, Canada and Europe.
In addition to these technical aspects, conducting standard, manual cervical cancer screening requires a sufficient quantity of qualified cytotechnologists and cytopathologists. This quantity will determine the volume of Pap smear slides that can reasonably be screened by such trained personnel. While the Clinical Laboratory Improvement Amendment of 1988 limits the number of slides that can be reviewed in an eight-hour day to 100, such a level of productivity is highly unlikely (Rosenthal D L, Automation and the endangered future of the Pap test. J Natl Cancer Inst 1998; 90:738-749.) A more reasonable optimal number is 60 per day, while an average would be 40-50. This translates into an individual cytotechnologist having the capacity to screen 10,000-14,000 slides per year. In the United States there are approximately 4,800 certified cytotechnologists. Although there is presently a slight shortage of qualified personnel in this field, this is an adequate number to screen the 50-60 million Pap smears done every year.
However, many areas of the world lack qualified and adequately trained cytotechnologists and cytopathologists. This shortage is often a result of the lack of training infrastructure and the low reimbursement rate for such screening tests (Bartels P H. Automation of primary screening for cervical cancer: sooner or later? Acta Cytol 1999; 43(1):7-12.) Such a situation makes it unlikely that women at risk will have adequate access to screening, or any access at all.
An example of a country in which there is such a lack of qualified cytotechnologists and cytopathologists is the United Arab Emirates. The total population of the United Arab Emirates (UAE) is approximately four million people. To screen one-third of the adult women of this country (representative of screening of every woman of screenable age once every three years) roughly 300,000 Pap smears per year would need to be done. The standard screening method would require 20-30 cytotechnologists doing nothing but Pap smears. Presently there are 15 hospitals and 15 clinical laboratories in the UAE. There are only 44 M.D. pathologists in the entire country, and very few of these are likely to be cytopathologists. While exact figures are lacking, it is reasonable to assume that, at most, only half of the hospitals and laboratories have even one cytotechnologist. Based on this assumption, at most, the UAE possesses a maximum of 15 cytology technicians. This assumption is supported by the fact that very few Pap smears are presently done in the United Arab Emirates. It is clear that this country does not have the qualified technical people to accommodate all the women who would need to be tested if population screening were to be performed. In addition, new laboratory infrastructure, including cytotechnologist workstations and equipment would also need to be created.
The inventors have developed new methods for providing medical screening, for example cervical cancer screening. In the case of cervical cancer screening, these methods provide excellent sensitivity and specificity in cervical cancer screening, and provide a cost-effective way of delivering mass cervical screening to areas of the world where a lack of sufficient laboratory infrastructure and technical skills presently compromises the effectiveness of screening or even makes mass screening impossible. It is thus hoped that these methods will significantly impact the rate of cervical cancer deaths in developing countries.
Methods of the invention separate cervical cancer screening task into two major segments: (1) sampling, slide preparation and an initial screening of slides, all of which are done by automation at a first geographic location (typically locally in a developing country); and (2) detailed reading of suspicious cells and report generation, which is performed by human experts at a second geographic location (typically at a remote site in a country that has adequate technical expertise). The first segment is supported by a highly automated system that provides a high quality slide and an automated, first-pass identification and elimination of normal smears, without requiring a highly trained technical staff. The second segment takes place at a remote site where highly-trained cytotechnologists and expert cytopathologists receive Internet-based, high-resolution digital images of suspicious cells or cell clusters, provide interpretation of results, and create reports based on these findings.
The great advantage of this segmented screening approach is that the expertise of medical institutions in industrialized countries can be brought to bear on samples from geographic areas that lack technical proficiency, or in which it is prohibitively expensive to recruit and maintain qualified medical personnel.
In some implementations, workflow and reporting is integrated through an Internet-based communication system and an automated messaging system.
Broadly, the invention features a method of providing a medical interpretation of each of a number of images associated respectively with different patients, including: (a) in a first geographic location, automatically screening diagnostic test data associated with the patients to screen out test data for which the medical interpretation is negative, and automatically producing digital images associated with test data that is likely to be indicative of abnormality, (b) transmitting the digital images electronically to a second geographic location, the medical interpretation for these digital images being possibly positive; (c) at the second geographic location, presenting the digital images to an experienced person to evaluate the images and confirm or reject the possibly positive medical interpretation; and (d) returning the medical interpretation electronically to the first geographic location. The first geographic location is one in which the automatic screening is legally permitted to be done as part of a medical diagnosis, and in which the number of experienced people capable of generating the medical interpretation as a ratio of the population needing screening is lower than in the second geographic location.
In one aspect, the invention features a method of providing a medical interpretation of each of a number of Pap smear slides, each slide including cellular material. The method includes: (a) in a first geographic location, automatically screening the Pap smear slides to screen out slides for which the medical interpretation is negative and automatically processing the remaining slides to produce digital images of cellular features that are likely to be indicative of abnormality; (b) transmitting the digital images electronically to a second geographic location, the medical interpretation for these digital images being possibly positive; (c) at the second geographic location, presenting the digital images to an experienced person to evaluate the images and confirm or reject the possibly positive medical interpretation; and (d) returning the medical interpretation electronically to the first geographic location. The first geographic location is one in which the automatic screening is legally permitted to be done as part of a medical diagnosis, and in which the number of experienced people capable of generating the medical interpretation as a ratio of the population needing screening is lower than in the second geographic location.
Implementations of this aspect of the invention may include one or more of the following features. The first geographic location is a developing country. The second geographic location is an industrialized country. Each raw image data file includes images of cells, and the method further includes, prior to electronic transmission of the remaining files, processing the remaining files to select for transmission images of cells which are most likely to result in a positive medical interpretation. The experienced person is a cytotechnologist or cytopathologist. The transmitting and returning steps are performed via the Internet, or, alternatively, by email. The method further includes preparing the Pap smears using a liquid-based thin-film sample preparation process, e.g., using an automated system. High volumes of Pap smears are processed at a low cost. The remaining files (the files that are manually reviewed) represent less than about 50% of the Pap smears.
In another aspect, the invention features a method for providing a medical interpretation for cervical cancer including: (a) receiving, at a second geographic location, an electronic transmission of a file from a first location, the file including information identifying a patient and images of cells sampled from the cervix of the patient, the file having been automatically screened, prior to transmission, so that the file is only transmitted if it contains cells for which the medical interpretation is possibly positive, (b) generating a medical interpretation of the images, the generating step being performed by an experienced person, and (c) transmitting the medical interpretation electronically to the first geographic location. The first geographic location is one in which the number of experienced people capable of generating the medical interpretation as a ratio of the population needing screening is lower than in the second geographic location, and in which the automatic screening is legally permitted to be done as part of a medical diagnosis.
The invention also features a method of providing a medical interpretation of each of a number of Pap smears, by utilizing the facilities at a remote geographic location, including: (a) in a first geographic location, automatically screening the Pap smear slides to screen out slides for which the medical interpretation is negative, and automatically processing the remaining slides to produce digital images of cellular features that are likely to be indicative of abnormality, (b) transmitting the digital images electronically to the remote geographic location for medical interpretation, the medical interpretation for these digital images being possibly positive, and (c) receiving the medical interpretation electronically from the remote geographic location. The first geographic location is one in which the automatic screening is legally permitted to be done as part of a medical diagnosis, and in which the number of experienced people capable of generating the medical interpretation as a ratio of the population needing screening is lower than in the remote geographic location.